The compound 4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-yl)-3-fluorobenzonitrile of the formula I
is described in WO2007/024945, WO2011/088188, WO2013/109514 and in E. L. Meredith et al., ACS Med. Chem. Lett. 2013, 4, 1203-1207. (R)-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluorobenzonitrile of formula Ia can be used as an aldosterone synthase (CYP11B2) inhibitor in the treatment of diseases and disorders characterized by increased stress hormone levels, such as in Cushing's syndrome, Cushing's disease and hypercortisolemia.

For marketing products, it is necessary to produce pharmaceuticals in large quantities. Hence, short and high-yielding syntheses are of utmost importance.
The compound 4-((5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-3-fluorobenzonitrile of the formula II
is a valuable intermediate for the production of 4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-yl)-3-fluorobenzonitrile (formula I). Hence, WO2007/024945 and Meredith et al., ACS Med. Chem. Lett. 2013, 4, 1203-1207 disclose a process for the production of 4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-yl)-3-fluorobenzonitrile (formula I), whereby the benzylic position of the compound of formula II is activated by the installation of an auxiliary ester moiety to give methyl 2-(5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-imidazol-1-yl)-2-(4-cyano-2-fluorophenyl)acetate (formula III).

Subsequent removal of the silyl protecting group from the compound of formula III, followed by mesylation of the resulting primary alcohol yields methyl 2-(4-cyano-2-fluorophenyl)-2-(5-(2-((methylsulfonyl)oxy)ethyl)-1H-imidazol-1-yl)acetate (formula IV), which upon treatment with base undergoes cyclization to afford methyl 5-(4-cyano-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylate (formula V). The compound of formula V is transformed into the compound of formula I by saponification of the methyl ester group followed by decarboxylation.

In respect of the synthetic route shown above it is important to note that attempts at cyclizing 4-((5-(2-chloroethyl)-1H-imidazol-1-yl)methyl)-3-fluorobenzonitrile (formula VI) by reacting it with a base, which would constitute a shorter route towards the compound of formula I, resulted in HCl elimination rather than cyclization, as reported by Meredith et al. (ACS Med. Chem. Lett. 2013, 4, 1203-1207).

It follows that activation of the benzylic position prior to cyclization, like in the known process where an auxiliary ester moiety is introduced into the compound of formula II (vide supra), is crucial. However, introduction and removal of said ester moiety requires three additional synthetic steps. In conclusion, the known route towards the compound of formula I is not ideal for industrial scale up.
Therefore, it would be highly advantageous to find a more efficient, that is, shorter, process for the production of 4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-yl)-3-fluorobenzonitrile (formula I).